FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy
Abstract Protein O-GlcNAcylation is a post-translational modification coupled to cellular metabolic plasticity. Aberrant O-GlcNAcylation has been observed in many cancers including endometrial cancer (EC), a common malignancy in women. However, clinical characterization of dysregulated O-GlcNAcylati...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56633-z |
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| author | Na Zhang Yang Meng Song Mao Huiling Ni Canhua Huang Licong Shen Kun Fu Lu Lv Chunhong Yu Piyanat Meekrathok Chunmei Kuang Fang Chen Yu Zhang Kai Yuan |
| author_facet | Na Zhang Yang Meng Song Mao Huiling Ni Canhua Huang Licong Shen Kun Fu Lu Lv Chunhong Yu Piyanat Meekrathok Chunmei Kuang Fang Chen Yu Zhang Kai Yuan |
| author_sort | Na Zhang |
| collection | DOAJ |
| description | Abstract Protein O-GlcNAcylation is a post-translational modification coupled to cellular metabolic plasticity. Aberrant O-GlcNAcylation has been observed in many cancers including endometrial cancer (EC), a common malignancy in women. However, clinical characterization of dysregulated O-GlcNAcylation homeostasis in EC and interrogating its molecular mechanism remain incomplete. Here we report that O-GlcNAcylation level is positively correlated with EC histologic grade in a Chinese cohort containing 219 tumors, validated in The Cancer Genome Atlas dataset. Increasing O-GlcNAcylation in patient-derived endometrial epithelial organoids promotes proliferation and stem-like cell properties, whereas decreasing O-GlcNAcylation limits the growth of endometrial cancer organoids. CRISPR screen and biochemical characterization reveal that tumor suppressor F-box only protein 31 (FBXO31) regulates O-GlcNAcylation homeostasis in EC by ubiquitinating the O-GlcNAc transferase OGT. Downregulation of O-GlcNAcylation impedes EC tumor formation in mouse models. Collectively, our study highlights O-GlcNAcylation as a useful stratification marker and a therapeutic vulnerability for the advanced, poorly differentiated EC cases. |
| format | Article |
| id | doaj-art-76843f93ebcf42fb8cceafb9130b7ca2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-76843f93ebcf42fb8cceafb9130b7ca22025-02-02T12:32:11ZengNature PortfolioNature Communications2041-17232025-02-0116112210.1038/s41467-025-56633-zFBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancyNa Zhang0Yang Meng1Song Mao2Huiling Ni3Canhua Huang4Licong Shen5Kun Fu6Lu Lv7Chunhong Yu8Piyanat Meekrathok9Chunmei Kuang10Fang Chen11Yu Zhang12Kai Yuan13Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityCenter for Medical Genetics, School of Life Sciences, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityHunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South UniversityAbstract Protein O-GlcNAcylation is a post-translational modification coupled to cellular metabolic plasticity. Aberrant O-GlcNAcylation has been observed in many cancers including endometrial cancer (EC), a common malignancy in women. However, clinical characterization of dysregulated O-GlcNAcylation homeostasis in EC and interrogating its molecular mechanism remain incomplete. Here we report that O-GlcNAcylation level is positively correlated with EC histologic grade in a Chinese cohort containing 219 tumors, validated in The Cancer Genome Atlas dataset. Increasing O-GlcNAcylation in patient-derived endometrial epithelial organoids promotes proliferation and stem-like cell properties, whereas decreasing O-GlcNAcylation limits the growth of endometrial cancer organoids. CRISPR screen and biochemical characterization reveal that tumor suppressor F-box only protein 31 (FBXO31) regulates O-GlcNAcylation homeostasis in EC by ubiquitinating the O-GlcNAc transferase OGT. Downregulation of O-GlcNAcylation impedes EC tumor formation in mouse models. Collectively, our study highlights O-GlcNAcylation as a useful stratification marker and a therapeutic vulnerability for the advanced, poorly differentiated EC cases.https://doi.org/10.1038/s41467-025-56633-z |
| spellingShingle | Na Zhang Yang Meng Song Mao Huiling Ni Canhua Huang Licong Shen Kun Fu Lu Lv Chunhong Yu Piyanat Meekrathok Chunmei Kuang Fang Chen Yu Zhang Kai Yuan FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy Nature Communications |
| title | FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy |
| title_full | FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy |
| title_fullStr | FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy |
| title_full_unstemmed | FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy |
| title_short | FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy |
| title_sort | fbxo31 mediated ubiquitination of ogt maintains o glcnacylation homeostasis to restrain endometrial malignancy |
| url | https://doi.org/10.1038/s41467-025-56633-z |
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